Implementing the NICE Guideline on Colorectal Cancer in the Context of Subsequent Developments

Dr Michael Braun and Dr Claire Arthur Assess Key Recommendations in the NICE Guideline on Colorectal Cancer, and Discuss Advances in Treatment and Management Since its Publication

Between 2016 and 2018, colorectal cancer was responsible for nearly 43,000 cancer cases in the UK, and was the fourth most common form of cancer.¹ In the same period, it caused more than 16,000 deaths annually; this represented 10% of all cancer-related deaths between 2017 and 2019, with colorectal cancer the second most common cause.¹

NICE Guideline (NG) 151 was published in January 2020 as an update to Clinical Guideline 131, published in 2011, to reflect advances in the treatment and management of colorectal cancer.² The guidance is largely applicable to secondary care, although the advice will be of interest to any stakeholder with an interest in colorectal cancer. This article focuses on recommendations relating to radiotherapy and systemic treatment for colorectal cancer.

Preoperative Treatment for Rectal Cancer

The NICE guideline committee looked at the evidence for radiotherapy or chemoradiotherapy as neoadjuvant therapy for more advanced cancers—either cancers with radiological evidence of nodal involvement (cN1–2), or more locally advanced disease, such as disease that goes beyond the muscularis propria (cT3) into the surrounding fat, or invades a surrounding organ (cT4). The relative benefits of radiotherapy alone compared with chemoradiotherapy, and the effects of different schedules of radiotherapy (short versus long courses), were also analysed.²

A significant drawback is that the quality of the data published in colorectal cancer trials is insufficient to allow the comparison of outcomes based on the stage or location of cancer (upper, mid, or lower rectum). Analysis of the combined data from all eligible studies showed a significant advantage in terms of lower recurrence rates and higher survival in patients who had received either radiotherapy or chemoradiotherapy for node‑positive or cT3–4 rectal cancer. But, because of the quality of the evidence, the committee could not refine its recommendation any further for location of cancer, grade of cancer, or other clinical variables. Toxicity of radiotherapy should be taken into account when considering the risk–benefit ratio of treatment (see Table 1).

Table 1: Acute and Late-onset Side-effects and Risks of Colorectal Radiotherapy

Neoadjuvant Treatment for Locally Advanced Colon Cancer

The guideline advises that preoperative chemotherapy should be considered for patients with clinical stage T4 tumours on initial imaging.² This recommendation was based on published evidence that neoadjuvant chemotherapy is safe, and may be associated with a greater chance of achieving clear resection margins.³ At the time of committee review, publication of the final results of the FOxTROT trial^4,5was pending—this trial randomised patients with bulky T3–T4 colon cancers between standard management (surgery followed by chemotherapy) or 6 weeks of neoadjuvant chemotherapy, followed by surgery, and then completion of chemotherapy.⁴ Unfortunately, only the results of the pilot study were available for consideration by the committee, and the full trial results are still to be published. Follow on trials have been funded and are now open, with the FOxTROT2 and FOxTROT3 studies ongoing.⁶

Duration of Postoperative Adjuvant Chemotherapy

Adjuvant chemotherapy following primary tumour resection is recommended for stage 3 colorectal cancers,⁷ but can be associated with significant side‑effects, such as peripheral neuropathy. The guideline made recommendations on the duration of adjuvant chemotherapy used for colorectal cancer based on data from the IDEA collaborative.⁸ This pooled analysis of six prospective randomised trials included 12,834 patients randomised between 3 and 6 months of treatment.⁸ The study demonstrated differences in outcome based on the choice of chemotherapy, which was not randomised; however, given the size of the study, the committee felt that it was reasonable to consider these subgroup analyses. No difference between disease‑free survival was observed between oxaliplatin/capecitabine given for 3 months compared with a 6‑month course. However, 6 months of oxaliplatin/fluorouracil (5FU) was superior to 3 months’ treatment (hazard ratio 1.16, 95% confidence interval 1.06–1.26, p=0.001). A 6‑month course of oxaliplatin was associated with a significantly increased risk of severe side‑effects.⁸ Therefore, for patients being considered for combination chemotherapy, a 3‑month course of oxaliplatin/capecitabine is the preferred choice in NG151.² A 3‑ to 6‑month course of oxaliplatin/5FU could be offered following assessment of a patient’s fitness and risk factors for recurrence, and a discussion on the risks and benefits.^2,8 For patients who are not considered for adjuvant combination chemotherapy, NG151 recommends a 6‑month course of capecitabine, in line with previous NICE guidance.^2,7

Systemic Treatment of Patients with Advanced Disease

The systemic treatment of advanced colorectal cancer, as defined by the existing technology appraisals at the time the guidance was published, was unaffected by NG151 (see Table 2).^7,9–13

Table 2: NICE Technology Appraisals and Their Influence on Colorectal Cancer Practice^7,9–16

The guideline formally recommends the routine testing of RAS (KRAS and NRAS) mutations as a predictive biomarker to select patients for first‑line epidermal growth factor receptor inhibitor (EGFRi) treatment. Additionally, testing of the BRAF V600E mutation was recommended because a pooled analysis demonstrated that the presence of this mutation is predictive of lack of benefit from EGFRi‑based treatment.²

Surgery and Ablation in the Advanced Disease Setting

Surgery and ablation are often considered for the management of patients with a small number of metastases in the liver, lungs, or peritoneal cavity. The guideline committee reviewed all three of these treatment areas to make recommendations, but recognised that the data to support the use of these interventions are often of low quality.²

For patients with operable liver‑only metastases, NG151 recommends liver resection be considered after discussion by a specialist multidisciplinary team (MDT). A course of perioperative chemotherapy can be considered, based on evidence that chemotherapy improves disease‑free survival, although there was uncertainty about whether it improves overall survival. For patients deemed unsuitable for resection—for example, because of comorbidities or lack of fitness—chemotherapy can be considered, combined with ablation of liver metastases, as an alternative to surgery.²

The use of first‑line selective internal radiation therapy (SIRT) in patients unsuitable for surgery or ablation was not recommended based on data from phase 3 trials, which demonstrated no improvement in overall survival.¹⁷ SIRT can still be offered to patients who have had prior treatment and fulfil NHS Commissioning Through Evaluation criteria.¹⁸ For patients with metastatic disease limited to the peritoneal cavity, it was deemed appropriate to offer an initial course of chemotherapy, and within the MDT meeting to discuss referral to a nationally commissioned specialist unit for consideration for cytoreductive surgery and heated intraperitoneal chemotherapy. It was agreed that only centres that have the necessary training and resources should offer this procedure.² The committee recognised that only a small number in England are currently able to do so; therefore, expansion of existing units and development of new specialist centres may be required over time.

For patients with colorectal cancer metastases to the lung, referral to a specialist MDT to consider metastasectomy, ablation, or stereotactic body radiation therapy (SABR) was recommended.² Although the guideline development committee were aware of the PULMICC trial (Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer); a feasibility study assessing the ability to randomise patients between surgery and surveillance, including chemotherapy; the study closed due to poor recruitment, and findings were published after the guideline.¹⁹ The PULMICC authors noted higher rates of survival in the surveillance arm of the study and called into doubt the benefits of surgery and ablation.²⁰ The committee recognised that the data available to support a recommendation were of low quality, and therefore a weak recommendation was made, but also concluded that the PULMICC trial data were not sufficiently powered to alter the recommendation.²¹

Finally, the committee also examined the role of surgical resection of an asymptomatic primary tumour in patients with established metastatic disease, and recommended that it be considered following discussion of the advantages and disadvantages with patients. Randomised trials have been difficult to perform in this context and, although non‑randomised case series or retrospective reviews have suggested that there may be an improvement in survival associated with resection, it is possible that the differences observed were due to confounding factors, such as patient fitness, comorbidity, or surgical considerations.²

Quality Standard

An initial review of the Quality Standard on colorectal cancer was delayed due to the COVID-19 pandemic, and was undertaken in 2021, with publication in 2022. It highlights four key areas for service development to ensure high quality care. These are:

• testing for lynch syndrome
• discussion about treatment options for early rectal cancer
• testing to guide systemic anti-cancer treatment
• follow up for detecting local recurrence and distant metastases.²²

Subsequent Developments and Research Priorities

The committee formally recommended that for patients with lung metastases, further research to compare the cost‑effectiveness and safety of non‑surgical ablation and SABR compared with surgical resection would be helpful.²

In 2021, a number of new treatment options were approved by NICE following positive technology appraisals (see Table 2).^14–16 Approximately 8% of metastatic colorectal cancer patients have a BRAF V600E mutation, and encorafenib plus cetuximab has been approved as second- or third-line treatment for these patients after demonstrating improved efficacy, objective response rate, and progression-free survival, compared with standard chemotherapy, and an improvement in overall survival.^23,24 Patients with mismatch repair deficient (MMRd) or microsatellite instability high (MSI-high) tumours constitute approximately 4% of advanced colorectal cancer patients,²⁵ but benefit significantly from immunotherapy.²⁶ Following publication of the Keynote-177 randomised phase III trial, pembrolizumab has been approved as a first-line treatment option.²⁷ Nivolumab with ipilimimab has also been approved as a second-line treatment, or beyond, for patients who have not previously received immunotherapy.²⁸

Further clinical trials are now underway in the UK to follow on from the FOxTROT study. These aim to assess the benefits of neoadjuvant chemotherapy in patients with locally advanced colon cancer.²⁹ The FOxTROT-2 study aims to randomise elderly or frail patients to upfront chemotherapy or immediate surgery.⁶ The FOxTROT-3 study aims to randomise fit patients to intensified three-drug chemotherapy or standard two-drug chemotherapy, as used in the original FOxTROT trial.⁶

When looking at the evidence for preoperative radiotherapy for rectal cancer, the guideline committee felt that future research should prospectively stratify the disease based on the biological type of cancer and its location within the rectum. It was also felt that there is a need for better prospective data to define patients who can be managed safely without the need for resective surgery after a complete (or near complete) clinical response following (chemo‑) radiation for rectal cancer. Deferral of surgery and organ preservation is an important aim for both patients and clinicians, and international consensus recommendations regarding key outcome measures for organ preservation following neoadjuvant treatment for rectal cancer are now available, providing a standardised assessment of complete response which may enable outcomes from future organ preservation trials to be compared.³⁰

Since the publication of the guidance in 2020, several trials have reported outcomes following total neoadjuvant therapy (TNT) for rectal cancer. This neoadjuvant schedule adopts both preoperative radiotherapy and chemotherapy, delivered sequentially. Decisions around patient selection and the optimal TNT approach remain under discussion—clinical trials have adopted varying TNT schedules using different radiotherapy schedules, chemotherapy regimens, and treatment sequencing. In addition, various endpoints have been evaluated, such as pathological complete response rates, disease-related treatment failure, disease-free survival, and organ preservation rates. Consideration of patient and tumour characteristics is key when adopting a TNT approach, in view of the reported toxicity.^31–33

Conclusion

Outcomes for patients with colorectal cancer have improved significantly since the 1970s. This is the result of a large number of incremental advances, such as improved preoperative staging and treatment selection, enhanced surgical techniques and training, introduction of systemic treatments in the adjuvant and palliative settings, and the establishment of a National Bowel Cancer Screening Service.³⁴

NICE guidelines and technology appraisals set a framework for best practice that supports clinicians and commissioners with developing local services and minimising variation in practice. This involves the further development of regional and national services to consider specialist surgery for metastatic disease—for example, liver, lung, and peritoneal surgery.

Radiotherapy practice across England and Wales varies significantly, largely because evidence from phase III randomised controlled trials has lagged behind the advances in clinical practice driven by large observational studies. This is a limitation of the current guidance, and was acknowledged by the committee. Nevertheless, the evidence review process was detailed and robust, and will be helpful for researchers when designing future trials to address the gaps in the current published studies.

Although there remains some variation regarding the indication and schedule of neoadjuvant radiotherapy, the technical delivery of radiotherapy across the UK was addressed in national guidance from the Royal College Radiologists in 2021.³⁵ Following a UK audit of current radiotherapy practice,³⁶ key recommendations, including patient preparation, treatment contouring, and delivery have been made.³⁵

For systemic treatment, the guidance provides useful recommendations regarding the use and duration of adjuvant chemotherapy, and the use of neoadjuvant chemotherapy for colon cancer. Technology appraisals will continue to play a key role in the use of systemic treatment in England and Wales.

Dr Michael Braun
Consultant Medical Oncologist, The Christie NHS Foundation Trust

Dr Claire Arthur
Consultant Clinical Oncologist, The Christie NHS Foundation Trust

This is an update of an article first published in Specialised Medicine (Misra V, Braun M. November 2020; 4 (4): 13–16).